Alzheimer disease neuropathology in a patient previously treated with aducanumab.
Aged, 80 and over
Alzheimer Disease
/ diagnostic imaging
Amyloid
/ metabolism
Amyloid beta-Peptides
/ metabolism
Antibodies, Monoclonal, Humanized
/ therapeutic use
Clinical Trials, Phase I as Topic
Female
Humans
Neurofibrillary Tangles
/ pathology
Plaque, Amyloid
/ pathology
Positron-Emission Tomography
Randomized Controlled Trials as Topic
Alzheimer disease
Amyloid PET
Amyloid beta
Case report
Immunotherapy
Neuropathology
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
27
01
2022
accepted:
05
05
2022
revised:
05
05
2022
pubmed:
18
5
2022
medline:
25
6
2022
entrez:
17
5
2022
Statut:
ppublish
Résumé
Amyloid beta (Aβ) plaque is a defining pathologic feature of Alzheimer disease (AD). Aducanumab, a monoclonal IgG1 that selectively binds aggregated species of Aβ, has been shown by amyloid positron emission tomography (Amyloid PET) to reduce Aβ plaques in patients with prodromal and mild AD. This is the first autopsy report of the AD neuropathology in a patient previously treated with aducanumab. The patient was an 84-year-old woman who was randomized to the placebo arm of the PRIME Phase 1b study (221AD103). The patient progressed to moderate dementia (MMSE = 14/30), beyond the targeted early AD treatment stage, before receiving aducanumab in the long-term extension (LTE). The patient then received 32 monthly doses of aducanumab, titrated up to 6 mg/kg, for a cumulative dose of 186 mg/kg. In the LTE, Amyloid PET scans demonstrated robust Aβ plaque reduction, from a composite standard uptake value ratio (SUVR) of 1.5 at screening to < 1.1 at 56 weeks post-aducanumab dosing. MRI examinations were negative for amyloid-related imaging abnormalities (ARIA). She passed away in hospice care 4 months after her last dose of aducanumab. The postmortem neuropathologic examination confirmed AD neuropathologic changes. Aβ and IBA1 immunohistochemistry assays demonstrated sparse residual Aβ plaque engaged by amoeboid reactive microglia. Phospho-Tau (pTau) immunohistochemistry demonstrated neocortical neurofibrillary degeneration (Braak stage V, NIA/AA Stage B3). However, the density of pTau neuropathology, including neuritic plaque pTau (NP-Tau), appeared lower in the PRIME LTE Patient compared to a reference cohort of untreated Braak stage V-VI, NIA/AA Stage B3 AD cases. Taken together, this case report is the first to provide Amyloid PET and neuropathologic evidence substantiating the impact of aducanumab to reduce Aβ plaque neuropathology in a patient with AD. Furthermore, this report underscores the critical importance of autopsy neuropathology studies to augment our understanding of aducanumab's mechanism of action and impact on AD biomarkers.
Identifiants
pubmed: 35581440
doi: 10.1007/s00401-022-02433-4
pii: 10.1007/s00401-022-02433-4
pmc: PMC9217863
doi:
Substances chimiques
Amyloid
0
Amyloid beta-Peptides
0
Antibodies, Monoclonal, Humanized
0
aducanumab
105J35OE21
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
143-153Subventions
Organisme : NIA NIH HHS
ID : P30 AG066508
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG047270
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Informations de copyright
© 2022. The Author(s).
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